Acute Lymphocytic Leukemia – Symptoms, Treatment

Acute Lymphocytic Leukemia (ALL) is a malignancy of B or T lymphoblasts characterized by uncontrolled proliferation of abnormal, immature lymphocytes and their progenitors which ultimately leads to the replacement of bone marrow elements and other lymphoid organs resulting in a typical disease pattern characteristic of Acute Lymphocytic Leukemia. ALL accounts for approximately 2 percent of the lymphoid neoplasms diagnosed in the United States. Acute Lymphocytic Leukemia occurs slightly more frequently in males than females, and three times as frequently in Whites as in Blacks. Patients with Acute Lymphocytic Leukemia typically present with symptoms related to anemia, thrombocytopenia, and neutropenia due to the replacement of the bone marrow with the tumor. Symptoms can include fatigue, easy or spontaneous bruising/bleeding, and infections. B-symptoms, such as fever, night sweats, and unintentional weight loss are often present but may be mild. Hepatomegaly, splenomegaly, and lymphadenopathy can be seen in up to half of adults on presentation. Central nervous system (CNS) involvement is common and can be accompanied by cranial neuropathies or symptoms, predominantly meningeal, related to increased intracranial pressure.[rx][rx][rx]

Types of Acute Lymphocytic Leukemia

Classification

French-American-British

Historically, prior to 2008, ALL was classified morphologically using the French-American-British (FAB) system that heavily relied on morphological assessment. The FAB system takes into account information on size, cytoplasm, nucleoli, basophilia (color of cytoplasm), and vacuolation (bubble-like properties).^[rx][rx]

While some clinicians still use the FAB scheme to describe tumor cell appearance, much of this classification has been abandoned because of limited impact on treatment choice and prognostic value.^[rx]:491

World Health Organization

In 2008, the World Health Organization classification of acute lymphoblastic leukemia was developed in an attempt to create a classification system that was more clinically relevant and could produce meaningful prognostic and treatment decisions. This system recognized differences in genetic, immunophenotype, molecular, and morphological features found through cytogenetic and molecular diagnostics tests.^{[rx]:1531–1535[rx]} This subtyping helps determine the prognosis and the most appropriate treatment for each specific case of ALL.

The WHO subtypes related to ALL are:^[rx]

• B-lymphoblastic leukemia/lymphoma
  • Not otherwise specified (NOS)
  • with recurrent genetic abnormalities
  • with t(9;22)(q34.1;q11.2);BCR-ABL1
  • with t(v;11q23.3);KMT2A rearranged
  • with t(12;21)(p13.2;q22.1); ETV6-RUNX1
  • with t(5;14)(q31.1;q32.3) IL3-IGH
  • with t(1;19)(q23;p13.3);TCF3-PBX1
  • with hyperdiploidy
  • with hypodiploidy
• T-lymphoblastic leukemia/lymphoma
• Acute leukemias of ambiguous lineage
  • Acute undifferentiated leukemia
  • Mixed phenotype acute leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1
  • MPAL with t(v;11q23.3); KMT2A rearranged
  • MPAL, B/myeloid, NOS
  • MPAL, T/myeloid, NOS

Causes of Acute Lymphocytic Leukemia

The etiology of Acute Lymphocytic Leukemia is unknown. However, certain environmental factors have been implicated in the etiology of Acute Lymphocytic Leukemia such as exposure to benzene, ionizing radiation, or previous exposure to chemotherapy or radiotherapy.

Genomic studies have noted that somatic, polymorphic variants of ARD5B, IKZF1 (the gene encoding Ikaros) and CDKN2A are associated with an increased risk of ALL (odds ratio 1.3 to 1.9). Other rare germline mutations in PAX5, ETV6, and particularly p53 can also strongly predispose to the development of leukemia.

Acute lymphoblastic Leukemia is not considered a familial disease and no screening programs have been developed to test for it in childhood.

or

Acute lymphocytic leukemia occurs when a bone marrow cell develops errors in its DNA. The errors tell the cell to continue growing and dividing, when a healthy cell would normally stop dividing and eventually die. When this happens, blood cell production becomes abnormal. The bone marrow produces immature cells that develop into leukemic white blood cells called lymphoblasts. These abnormal cells are unable to function properly, and they can build up and crowd out healthy cells.

It’s not clear what causes the DNA mutations that can lead to acute lymphocytic leukemia. But doctors have found that most cases of acute lymphocytic leukemia aren’t inherited.

Pathophysiology

Acute Lymphocytic Leukemia is thought to occur after damage to DNA causes lymphoid cells to undergo uncontrolled growth and spread throughout the body. Splenomegaly and hepatomegaly occur due to sequestration of platelets and lymphocytes in the spleen and liver as the white blood cells are not typical the spleen reacts to them by trying to remove them from the blood. [rx][rx][rx]

Symptoms of Acute Lymphocytic Leukemia

The early signs and symptoms of ALL may be like the flu or other common diseases. Check with your doctor if you have any of the following:

• Weakness or feeling tired.
• Fever or drenching night sweats.
• Easy bruising or bleeding.
• Petechiae (flat, pinpoint spots under the skin, caused by bleeding).
• Shortness of breath.
• Weight loss or loss of appetite.
• Pain in the bones or stomach.
• Pain or feeling of fullness below the ribs.
• Painless lumps in the neck, underarm, stomach, or groin.
• Having many infections.

The signs and symptoms of ALL are variable and include

• Generalized weakness and feeling tired
• Anemia
• Dizziness
• Headache, vomiting, lethargy, neck stiffness,^[rx] or cranial nerve palsies^[rx] (CNS involvement)
• Frequent or unexplained fever and infection
• Weight loss and/or loss of appetite
• Excessive and unexplained bruising
• Bone pain, joint pain (caused by the spread of “blast” cells to the surface of the bone or into the joint from the marrow cavity)
• Breathlessness
• Enlarged lymph nodes, liver and/or spleen
• Pitting edema (swelling) in the lower limbs and/or abdomen
• Petechiae, which are tiny red spots or lines in the skin due to low platelet levels
• Testicular enlargement
• Mediastinal mass

Diagnosis of Acute Lymphoblastic Leukemia

Histopathology

On peripheral blood smears of Acute Lymphocytic Leukemia patients, lymphoblasts vary in size. Various CD cytokines must be tested to evaluate for what kind of Acute Lymphocytic Leukemia the patient has developed

History and Physical

The most common presenting symptoms of Acute Lymphocytic Leukemia are nonspecific and may be difficult to distinguish from common, self-limited diseases of childhood. In a meta-analysis, more than half of children with childhood leukemia had at least one of the following five features on presentation: palpable liver, palpable spleen, pallor, fever, or bruising. ALL patients typically present with symptoms of night sweats, easy bruising, skin pallor, unexplained lymphadenopathy, weakness, weight loss, hepatosplenomegaly, or difficulty breathing. Some patients may present with Superior Vena Cava Syndrome. Bone pain, mental changes, and oliguria may also be present. ALL can also present with testicular enlargement, musculoskeletal pain, mediastinal mass, and incidentally found peripheral blood cell abnormalities.

Evaluation

Acute Lymphocytic Leukemia diagnosis should be explored initially with a laboratory evaluation consisting of a CBC, electrolyte and renal panel, and LDH level. Additionally, imaging such as a chest x-ray for symptoms of shortness of breath may be obtained. If abdominal fullness, tenderness or abdominal mass are symptoms, then a CT scan of the abdomen and pelvis should be obtained. This can also help with the staging of the disease.

NCCN diagnosis guidelines:

• Have presence of more than 20% bone marrow lymphoblasts
• Hematoxylin and eosin-stained bone marrow clot and biopsy sections
• Morphology of bone marrow aspirate assessed with Wright/Giemsa
• Complete flow cytometric immunophenotyping
• Baseline evaluation of the leukemic clone

Lumbar puncture is used to evaluate CNS involvement. The fluid is checked for the presence of lymphoblasts. Acute lymphocytic leukemia consultation

Tests and procedures used to diagnose acute lymphocytic leukemia include

• Blood tests – Blood tests may reveal too many white blood cells, not enough red blood cells and not enough platelets. A blood test may also show the presence of blast cells — immature cells normally found in the bone marrow.
• Bone marrow test – During bone marrow aspiration, a needle is used to remove a sample of bone marrow from the hipbone or breastbone. The sample is sent to a lab for testing to look for leukemia cells.
• Imaging tests – Imaging tests such as an X-ray, computerized tomography (CT) scan or ultrasound scan may help determine whether cancer has spread to the brain and spinal cord or other parts of the body.
• Spinal fluid test – A lumbar puncture test, also called a spinal tap, may be used to collect a sample of spinal fluid — the fluid that surrounds the brain and spinal cord. The sample is tested to see whether cancer cells have spread to the spinal fluid.
• Blood chemistry studies – A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
• Peripheral blood smear – A procedure in which a sample of blood is checked for blast cells, the number and kinds of white blood cells, the number of platelets, and changes in the shape of blood cells.
• Bone marrow aspiration and biopsy – The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for abnormal cells.
• CT scan (CAT scan) – A procedure that makes a series of detailed pictures of the abdomen, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
• MRI (magnetic resonance imaging) – A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).

Treatment of Acute Lymphoblastic Leukemia

Children who are suspected of having Acute Lymphocytic Leukemia should be referred to a pediatric center that specializes in cancer for evaluation and treatment.

For children with Acute Lymphocytic Leukemia, induction therapy consists of anthracycline, vincristine, 1-asparaginase, and a corticosteroid. Today consolidation therapy is widely used and include therapy with a variety of chemotherapeutic drugs with good results.

Maintenance therapy utilizes oral 6-mercaptopurine or methotrexate delivered once weekly or once monthly.  Successful treatment of children with Acute Lymphocytic Leukemia involves administration of a multidrug regimen that is divided into several phases (i.e., induction, consolidation, and maintenance) and includes therapy directed to the central nervous system (CNS).

Most treatment protocols take two to three years to complete. CNS prophylaxis is done via an intrathecal approach. Patients often require 8-16 intrathecal treatments.

If the patient has Ph-chromosome positive ALL, the current treatment includes the use of tyrosine kinase inhibitors like imatinib, nilotinib, dasatinib or ponatinib. Several trials have shown a good response to these agents.

Stem cell transplantation can sometimes be used as a treatment in which patient’s normal source of blood cells (bone marrow) is replaced by healthy young blood cells (stem cells) from a healthy well-matched donor. However, with improvements in chemotherapy, the role of transplantation is declining in ALL.

In general, treatment for acute lymphocytic leukemia falls into separate phases:

• Induction therapy – The purpose of the first phase of treatment is to kill most of the leukemia cells in the blood and bone marrow and to restore normal blood cell production.
• Consolidation therapy – Also called post-remission therapy, this phase of treatment is aimed at destroying any remaining leukemia in the body, such as in the brain or spinal cord.
• Maintenance therapy – The third phase of treatment prevents leukemia cells from regrowing. The treatments used in this stage are often given at much lower doses over a long period of time, often years.
• Preventive treatment to the spinal cord – During each phase of therapy, people with acute lymphocytic leukemia may receive additional treatment to kill leukemia cells located in the central nervous system. In this type of treatment, chemotherapy drugs are often injected directly into the fluid that covers the spinal cord.
• Radiation therapy – Your doctor might use high-energy radiation to kill cancer cells if they’ve reached your brain or bone or before you have a stem cell transplant. Radiation therapy uses high-powered beams, such as X-rays or protons, to kill cancer cells. If the cancer cells have spread to the central nervous system, your doctor may recommend radiation therapy.
• Immunotherapy – These drugs boost your immune system to kill or slow the growth of cancer cells. They include blinatumomab (Blincyto) and inotuzumab ozogamicin (Besponsa).
• A stem cell transplant – After high doses of chemotherapy and possibly radiation, you get stem cells that will grow into healthy blood cells. They might be your own or come from a donor. If you can’t handle high doses of chemotherapy and radiation, you might get lower doses with a “mini-transplant.”
• Chemotherapy – Chemotherapy, which uses drugs to kill cancer cells, is typically used as an induction therapy for children and adults with acute lymphocytic leukemia. Chemotherapy drugs can also be used in the consolidation and maintenance phases.
• Targeted therapy – Targeted drugs attack specific abnormalities present in cancer cells that help them grow and thrive. Some drugs target specific parts of cancer cells and tend to have fewer or milder side effects than chemotherapy. They include dasatinib (Sprycel), imatinib (Gleevec), nilotinib (Tasigna), and ponatinib (Iclusig).  A certain abnormality called the Philadelphia chromosome is found in some people with acute lymphocytic leukemia. For these people, targeted drugs may be used to attack cells that contain that abnormality. Targeted therapy may be used during or after chemotherapy.
• Bone marrow transplant – A bone marrow transplant, also known as a stem cell transplant, may be used as consolidation therapy in people at high risk of relapse or for treating relapse when it occurs. This procedure allows someone with leukemia to re-establish healthy bone marrow by replacing leukemic bone marrow with leukemia-free marrow from a healthy person. A bone marrow transplant begins with high doses of chemotherapy or radiation to destroy any leukemia-producing bone marrow. The marrow is then replaced by bone marrow from a compatible donor (allogeneic transplant).
• Recently CAR-T cell therapy – has been investigated in ALL with excellent results. Several studies show high rates of remission. Unfortunately, CART is also associated with serious toxicity that includes cerebral edema and cytokine release syndrome, which can be fatal. All blood products must be irradiated prior to transfusion to prevent transfusion-related graft versus host disease, which is universally fatal.
• Splenectomy – is rarely required for Acute Lymphocytic Leukemia. Splenectomy can help boost platelet count but does not affect the outcome of leukemia itself. Splenectomy can be performed for severe symptoms that are not amenable to chemotherapy treatment such as abdominal pain. Radiation can also be used in cases of the enlarged spleen to try and reduce the size of the spleen in most cases. [rx][rx][rx]

Tumor lysis syndrome is a life-threatening complication that occurs in patients receiving chemotherapy. It is characterized by hyperuricemia, elevated potassium and phosphate and decreased levels of calcium. Renal failure is invariably present.

Staging

Current World Health Organization Classification of ALL[rx]

B-lymphoblastic leukemia/lymphoma

• B-lymphoblastic leukemia/lymphoma, NOS
• B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
• B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);  BCR-ABL1
• B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged
• B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1);  ETV6-RUNX1
• B-lymphoblastic leukemia/lymphoma with hyperdiploidy
• B-lymphoblastic leukemia/lymphoma with hypodiploidy
• B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3);  IL3-IGH
• B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);  TCF3-PBX1
• Provisional entity: B-lymphoblastic leukemia/lymphoma,  BCR-ABL1-like
• Provisional entity: B-lymphoblastic leukemia/lymphoma with  iAMP21

T-lymphoblastic leukemia/lymphoma

• Provisional entity: Early T-cell precursor lymphoblastic leukemia
• Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma

staging should be performed using bone marrow, and lumbar puncture samples and treatment started immediately after confirmation of diagnosis.

St. Jude/Murphy Staging System (Children)

• Stage I: A single tumor (extranodal) or a single anatomical area (nodal), excluding mediastinum or abdomen or a tumor (extranodal) with regional node involvement, on the same side of the diaphragm.
• Stage II: A single tumour (extranodal) with regional node involvement, lymph node involvement on same side of the diaphragm (two or more nodal areas or two single extranodal tumours, with or without regional node involvement), or a primary gastrointestinal tract tumour (usually ileocecal) with or without associated mesenteric node involvement, grossly completely resected.
• Stage III: On both sides of the diaphragm (two or more nodal areas or two single extranodal tumours), all primary intrathoracic tumours (e.g., mediastinal or pleural thymic), all extensive primary intraabdominal disease; unresectable abdominal disease, even if only in one area, or all primary paraspinal or epidural tumours, irrespective of other sites.
• Stage IV: Any of the above with initial CNS or bone marrow involvement (only if less than 25% of the marrow is composed of Burkitt cells).[rx]

Murphy System (Adult)

• Stage I: Single nodal or extranodal site excluding the mediastinum or abdomen.
• Stage II: Two or more nodal areas on one side of the diaphragm.
• Stage IIR: Completely resectable abdominal disease
• Stage III: Two or more nodal areas on opposite sides of the diaphragm, or a primary intrathoracic tumor, paraspinal or epidural tumors, extensive intra-abdominal disease
• Stage IIIA: Completely non-resectable abdominal disease
• Stage IIIB: Widespread multiorgan intra-abdominal disease
• Stage IV: Central nervous system or bone marrow involvement

Favorable: Stage I or IIR[rx]

Ann Arbor System (Adult)

• Stage 1: Single nodal or extranodal site
• Stage II: Two or more nodal areas on one side of the diaphragm, or localized involvement of an extra-lymphatic site and one or more sites on the same side of the diaphragm (IIE)
• Stage III: Two or more nodal areas on opposite sides of the diaphragm which may include/ involvement of the spleen (IIIs), or localized involvement of an extranodal site (IIIE)
• Stage IV: Diffuse or disseminated involvement of one or more extra-lymphatic sites, or two single extranodal tumors on opposite sides of the diaphragm

Favorable: Stage I, II, III[rx]

Prognosis

Only about 30% of adults with ALL can be cured today. Criteria for good prognosis include:

• Age of less than 30
• No abnormal cytogenetics
• WBC count less than 30,000
• Complete remission within 4 weeks

Poor prognostic factors include:

• Age of more than 60
• Presence of abnormal cytogenetics (t(9:22), t(4:11)
• Failure to achieve remission within 4 weeks
• Precursor B-cells more than 100,000

References